Claims for Patent: 6,604,698

Summary for Patent: 6,604,698

Title:	Media milling
Abstract:	This invention describes a process for preparing a dispersion of solid particles of a milled substrate in a fluid carrier comprising the steps of (a) providing a plurality of large size milling media to the milling chamber of a media mill and forming a depth filter therefrom on an exit screen or separator in the milling chamber; (b) adding to said milling chamber a plurality of small size milling media optionally containing additional large size milling media, a conglomerate of a solid substance comprising a substrate to be milled and optionally one or more than one surface active substance, and a fluid carrier; (c) milling said conglomerate in said milling chamber to produce very small milled substrate product particles; and (d) separating said milled substrate particles suspended in said fluid carrier from the media through said depth filter; wherein the exit screen comprises openings of size S.sub.0 ; the large size media have a size distribution S.sub.1 of which all are larger than S.sub.0 ; the small size media have a size distribution S.sub.2 which are smaller than S.sub.0 ; the very small milled substrate particles have a size distribution S.sub.3 and are smaller than all of the small media; and the large size media and the small size media are essentially retained in the milling chamber.
Inventor(s):	Verhoff; Frank H. (Cincinnati, OH), Snow; Robert A. (West Chester, PA), Pace; Gary W. (Raleigh, NC)
Assignee:	SkyePharma Canada, Inc. (Montreal, CA)
Application Number:	09/852,054
Patent Claims:	1. A process for preparing a dispersion of solid particles of a milled substrate in a fluid carrier comprising the steps of: (a) providing a plurality of large size milling media to the milling chamber of a media mill and forming a depth filter therefrom on an exit screen or separator in the milling chamber; (b) adding to said milling chamber a plurality of small size milling media optionally containing additional large size milling media, a conglomerate of a solid substance comprising a substrate to be milled and optionally one or more than one surface active substance, and a fluid carrier; (c) milling said conglomerate in said milling chamber to produce very small milled substrate product particles; and (d) continuously removing or separating said milled substrate particles suspended in said fluid carrier from the media through said depth filter; wherein: the exit screen or separator comprises openings of size S.sub.0 ; the large size media have a size distribution S.sub.1 of which all are larger than S.sub.0 ; the small size media have a size distribution S.sub.2 which are smaller than S.sub.0 ; the very small milled substrate particles have a size distribution S.sub.3 and are smaller than all of the small media; and the large size media and the small size media are retained in the milling chamber. 2. The process of claim 1, wherein the fluid carrier is a liquid. 3. The process of claim 1, wherein the fluid carrier is selected from the group consisting of water, sterile water, water for injection, aqueous solutions of one or more salts, solutions of aqueous buffers, aqueous phosphate buffered saline, sugar-containing water, aqueous solutions of one or more pharmaceutical excipients, aqueous solutions of one or more carbohydrates, aqueous solutions of one or more polymers, aqueous solutions of one or more than one surface active substance, aqueous solutions of one or more surface active substances mixed with one or more undissolved liquid surface active substances, PEG-containing water, ethanol, methanol, butanol, hexane, hydrocarbons, kerosene, glycol, toluene, glyme, petroleum-based solvents, ligroin, mixtures of aromatic solvents, xylenes, toluene, heptane, mixtures of water miscible solvents and water, DMSO, DMF, and mixtures of these fluid carriers. 4. The process of claim 1, wherein the fluid carrier is sterile. 5. The process of claim 1, wherein the surface active substance is selected from the group consisting of phospholipids, natural surfactants, nonionic surfactants, anionic surfactants, cationic surfactants, and colloidal clays. 6. The process of claim 5, wherein the surface active substance is a phospholipid or mixture of phospholipids. 7. The process of claim 6, wherein the phospholipid is selected from the group consisting of egg lecithin, egg phosphatidylcholine, hydrogenated egg phosphatidylcholine, soy phosphatidylcholine, dimyristoylphosphatidylglycerol, and combinations thereof. 8. The process of claim 1, wherein the solid substance is selected from the group consisting of a solid pigment, a solid photographic material, a solid cosmetic ingredient, a solid support material, a solid toner material, and a solid pharmaceutical agent. 9. The process of claim 8, wherein the pharmaceutical agent is a therapeutic agent or a diagnostic imaging agent. 10. The process of claim 8, wherein the pharmaceutical agent is a poorly water-soluble drug, an essentially water-insoluble drug, or an insoluble drug. 11. The process of claim 9, wherein the pharmaceutical agent is selected from the group consisting of anesthetic agents, ace inhibiting agents, antithrombotic agents, anti-allergic agents, antibacterial agents, antibiotic agents, anticoagulant agents, anticancer agents, antidiabetic agents, antihypertension agents, antifungal agents, antihypotensive agents, antiinflammatory agents, antimitotic agents, antimigraine agents, antiparkinson agents, antirheumatic agents, antithrombins, antiviral agents, beta blocking agents, bronchospamolytic agents, calcium antagonists, cardiovascular agents, cardiac glycosidic agents, carotenoids, cephalosporins, contraceptive agents, cytostatic agents, diuretic agents, enkephalins, fibrinolytic agents, growth hormones, immunosuppressants, insulins, interferons, lactation inhibiting agents, lipid-lowering agents, lymphokines, neurologic agents, prostacyclins, prostaglandins, psycho-pharmaceutical agents, protease inhibitors, magnetic resonance diagnostic imaging agents, reproductive control hormones, sedative agents, sex hormones, somatostatins, steroid hormonal agents, vaccines, vasodilating agents, and vitamins. 12. The process of claim 8, wherein the pharmaceutical agent is selected from the group consisting of albendazole, albendazole sulfoxide, alfaxalone, acetyl digoxin, acyclovir, acyclovir analogs, aiprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin, benzocaine, benzocaine derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, binovum, biperiden, bromazepam, bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan, cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin, cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate, ciglitazone, clonidine, cortexolone, corticosterone, cortisol, cortisone, cyclophosphamide, cyclosporin A, cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone esters, dezocine, diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digitoxin, digoxin, dihydroergotamine, dihydroergotoxin, diltiazem, dopamine antagonists, doxorubicin, econazole, endralazine, enkephalin, enalapril, epoprostenol, estradiol, estramustine, etofibrate, etoposide, factor ix, factor viii, felbamate, fenbendazole, fenofibrate, flunarizin, flurbiprofen, 5-fluorouracil, flurazepam, fosfomycin, fosmidomycin, furosemide, gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide, glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine, hydralazine, hydrochiorothiazide, hydrocortisone, ibuprofen, ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray contrast agents, iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifen, ketotifen fumarate, K-strophanthin, labetalol, lactobacillus vaccine, lidoflazin, lisuride, lisuride hydrogen maleate, lorazepam, lovastatin, mefenamic acid, melphalan, memantin, mesulergin, metergoline, methotrexate, methyl digoxin, methylprednisolone, metronidazole, metisoprenol, metipranolol, metkephamide, metolazone, metoprolol, metoprolol tartrate, miconazole, miconazole nitrate, minoxidil, misonidazol, molsidomin, nadolol, nafiverine, nafazatrom, naproxen, natural insulins, nesapidil, nicardipine, nicorandil, nifedipine, niludipin, nimodipine, nitrazepam, nitrendipine, nitrocamptothesin, 9-nitrocamptothesin, oxazepam, oxprenolol, oxytetracycline, penicillins, penicillin G benethamine, penecillin O, phenylbutazone, picotamide, pindolol, piposulfan, piretanide, piribedil, piroxicam, pirprofen, plasminogenic activator, prednisolone, prednisone, pregnenolone, procarbacin, procaterol, progesterone, proinsulin, propafenone, propanolol, propentofyllin, propranolol, rifapentin, simvastatin, semi-synthetic insulins, sobrerol, somastotine, somatropin, stilamine, sulfinalol hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulproston, synthetic insulin, talinolol, taxol, taxotere, testosterone, testosterone propionate, testosterone undecanoate, tetracane HI, tiaramide HCl, tolmetin, tranilast, triquilar, tromantadine HCl, urokinase, valium, verapamil, vidarabine, vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine, vincristine, vindesine, vinpocetine, vitamin A, and vitamin E succinate. 13. The process of claim 8, wherein the pharmaceutical agent is selected from the group consisting of acyclovir, alprazolam, altretamine, amiloride, amiodarone, benztropine mesylate, bupropion, cabergoline, candesartan, cerivastatin, chlorpromazine, ciprofloxacin, cisapride, clarithromycin, clonidine, clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, desmopressin, diltiazem, dipyridamole, dolasetron, enalapril maleate, enalaprilat, famotidine, felodipine, furazolidone, glipizide, irbesartan, ketoconazole, lansoprazole, loratadine, loxapine, mebendazole, mercaptopurine, milrinone lactate, minocycline, mitoxantrone, nelfinavir mesylate, nimodipine, norfioxacin, olanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifampin, risperidone, rizatriptan, saquinavir, sertraline, sildenafil, acetyl-sulfisoxazole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimetrexate, troglitazone, trovafloxacin, verapamil, vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine, teniposide, and acetylsalicylate. 14. The process of claim 1, wherein the fluid carrier is selected from the group consisting of a gas, a liquefied compressed gas, a supercritical fluid, a supercritical fluid containing one or more dissolved excipients, and a supercritical fluid containing one or more surface active agents. 15. The process of claim 1, wherein the process comprises forming the depth filter on an exit screen comprising openings of less than 1 millimeter in size. 16. The process of claim 1, wherein the process comprises milling the conglomerate with large size media having a size that is at least 1.2 times larger than S.sub.0. 17. The process of claim 16, wherein the process comprises milling the conglomerate with a large size media having a size that is at least 1.5 times larger than S.sub.0. 18. The process of claim 17, wherein the process comprises milling the conglomerate with a large size media having a size that is at least 3 times larger than S.sub.0. 19. The process of claim 1, wherein the process comprises milling the conglomerate with a small size media having a size that is smaller than S.sub.0. 20. The process of claim 18, wherein the process comprises milling the conglomerate with a small size media having a size that is less than or equal to 0.95 times S.sub.0. 21. The process of claim 20, where in the process comprises milling the conglomerate with a small size media having a size that is less than or equal to 0.85 times S.sub.0. 22. The process of claim 1, wherein the process comprises milling the conglomerate in the milling chamber with a mixture of large milling media and small milling media, wherein the volume of large milling media makes up 1% to 95% of the total milling media volume in the milling chamber. 23. The process of claim 22, wherein the process comprises milling the conglomerate with a mixture of large and small milling media in which the volume of the large milling media makes up 10% to 85% of the total milling media volume in the milling chamber. 24. The process of claim 23, wherein the process comprises milling the conglomerate with a mixture of large and small milling media in which the volume of large milling media makes up 35% to 70% of the total milling media volume in the milling chamber. 25. The process of claim 1, wherein the process comprises producing and removing or separating milled substrate particles of less than 2 .mu.m in size. 26. The process of claim 25, wherein the process comprises producing and removing or separating milled substrate particles of less than 1 .mu.m in size. 27. The process of claim 26, wherein the process comprises producing and removing or separating milled substrate particles of less than 0.5 .mu.m in size. 28. The process of claim 27, wherein the process comprises producing and removing or separating milled substrate particles of less than 0.4 .mu.m in size. 29. The process of claim 28, wherein the process comprises producing and removing or separating milled substrate particles of less than 0.2 .mu.m in size. 30. The process of claim 1, wherein the process comprises milling the conglomerate with large size milling media selected from the group consisting of spheres, cylinders, and toroids. 31. The process of claim 1, wherein the process comprises milling the conglomerate with small size milling media selected from the group consisting of polymeric beads, glass beads, zirconium silicate beads, and steel beads.

Details for Patent 6,604,698

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
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